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Cervical cancer is a leading cause of cancer deaths in women worldwide. Because of its association with human papilloma virus infection, as well as the ability to screen for premalignant stages of the disease, it is now largely a preventable disease. This article describes the molecular basis for cervical cancer, and presents a clinical overview of current treatment approaches and technological advances, emphasizing the unique aspects of this viral disease as it relates to the immune system and vaccination or other immunotherapeutic strategies.

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During the past quarter-century, progress has occurred in the area of coordinated care of the patient with gynecologic cancer. This progress is the result of the refined surgical techniques and perioperative management of patients requiring intensive care after radical pelvic surgery. Furthermore, the addition of radiation therapy and chemotherapy has made major contributions to the improvement and quality of life for patients with gynecologic cancer. All formal training programs in gynecologic oncology now include appropriate rotations and experience with these newer techniques and treatment modalities. The gynecologic oncologist should be fully equipped to manage primary treatment and most of the complications related to the care of patients with gynecologic neoplasms. Formal training programs in gynecologic oncology have been fundamental in the attainment of this goal and provide the infrastructure for future developments. It is anticipated that continued worldwide surgical studies in the area of gynecologic oncology will improve the well-being of women who may have cancer.

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The aging of the population is a social phenomenon that will present a challenge to clinical practice in the 21st century. Women constitute a majority of the elderly population as they outlive males by 5 to 7 years. Ovarian, endometrial, and vulvar cancers are diseases seen more commonly in postmenopausal and elderly women. Cervical cancer continues to be a significant problem in the elderly and is usually detected at a later stage in that population than in younger patients. Accordingly, primary care clinicians ought to possess a thorough knowledge of gynecologic malignancies and should refer women who present with these disorders to a gynecologic oncologist. Ovarian cancer patients treated by a gynecologic oncologist are more likely to undergo proper surgical staging, leading to optimal debulking surgery and improved survival. Age, by itself, should not alter the diagnostic and therapeutic approach to gynecologic malignancy. Elderly patients can safely undergo radical pelvic surgery. Multiagent chemotherapy is also possible in the elderly without excess morbidity, and without compromise of response rates. Radiation therapy for cervical cancer appears to be as effective and is generally well tolerated. The Papanicolaou (Pap) test continues to be the primary screening tool for cervical cancer. Although transvaginal ultrasound seems to be useful in detecting early-stage ovarian cancer, its cost effectiveness for screening the general population remains to be demonstrated. The main considerations in the treatment of ovarian, endometrial, cervical, and vulvar cancer are discussed.

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OBJECTIVE: This study was conducted to analyze our experience with low (8-12 cm above the anal verge) and very low (<6 cm above the anal verge) colorectal resection and primary anastomosis at the time of radical en bloc resection of pelvic malignancies. STUDY DESIGN: A retrospective review of 77 patients undergoing supralevator pelvic exenteration with low colorectal resection and primary anastomosis in our gynecologic oncology service was carried out. Data were obtained from patient medical records and from the tumor registry. Univariate statistical analysis of the data was used. RESULTS: The distribution of primary malignancies in this cohort was as follows: 33 (43%) recurrent or primary cervical carcinomas, 27 (35%) primary or recurrent ovarian carcinomas, 7 (9%) recurrent vaginal carcinomas, 4 (5%) endometrial carcinomas, 3 (4%) colon carcinomas, and 3 (4%) cases of stage IV endometriosis. Forty patients underwent total pelvic exenteration, and 37 patients underwent posterior exenteration. Thirty-six patients in the total pelvic exenteration group had a history of pelvic irradiation. Twelve (30%) of these patients had development of breakdown or fistulas of the anastomosis. Six of the 12 patients (50%) had undergone protective colostomy. Thirty-seven patients underwent posterior exenteration with primary anastomosis for ovarian cancer, endometrial cancer, colon cancer, or endometriosis, and only 1 of these had received pelvic irradiation. This patient did not have a protective colostomy, and a rectovaginal fistula developed. In addition, there were 3 other breakdowns in the posterior exenteration group. Finally, the presence of preoperative ascites did not appear to alter the breakdown rate of the anastomosis among the patients with ovarian cancer who underwent cytoreductive surgery. CONCLUSION: Radical resection of pelvic tissue remains a crucial part of the armamentarium of the gynecologic oncologist. Previous pelvic irradiation appears to be a major risk factor (35% vs 7.5%) for anastomotic breakdown and fistulas, independent of the presence of a protective colostomy. The overall results appear to be better for patients undergoing this procedure as part of a posterior exenteration.

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PURPOSE: To determine if patients with carcinoma of the vulva, with N2/N3 lymph nodes, could undergo resection of the lymph nodes and primary tumor following preoperative chemo-radiation. METHODS AND MATERILAS: Fifty-two patients were entered in the study, but six patients did not meet the criteria of the protocol and were excluded. The remaining 46 patients are the subject of this report. Patients underwent a split course of radiation, 4760 cGy to the primary and lymph nodes, with concurrent chemotherapy, cisplatin/5-FU, followed by surgery. RESULTS: Four patients did not complete the chemo-radiation, because three expired and one refused to complete the treatment. Four patients who completed chemo-radiation did not undergo surgery, because two of them died of non-cancer-related causes, and in the other two patients, the nodes remained unresectable. Following chemo-radiation, the disease in the lymph nodes became resectable in 38/40 patients. Two patients who completed the course of chemo-radiation did not undergo surgery as per protocol because of pulmonary metastasis. One underwent radical vulvectomy and unilateral node dissection and the other radical vulvectomy only. The specimen of the lymph nodes was histologically negative in 15/37 patients. Nineteen patients developed recurrent and/or metastatic disease. The sites of failure were as follows: primary area only, 9; lymph node area only, 1; primary area and distant metastasis, 1; distant metastasis only, 8. Local control of the disease in the lymph nodes was achieved in 36/37 and in the primary area in 29/38 of the patients. Twenty patients are alive and disease-free, and five have expired without evidence of recurrence or metastasis. Two patients died of treatment-related complications. CONCLUSION: High resectability and local control rates of the lymph nodes were obtained in patients with carcinoma of the vulva with N2/N3 nodes treated preoperatively with chemo-radiation.

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OBJECTIVE: To determine whether the prevalence of normal endometrial cells in Papanicolaou smears of women with and those without endometrial carcinoma or hyperplasia differs significantly. METHODS: Papanicolaou smears of women with biopsy-proved endometrial hyperplasia or carcinoma diagnosed between 1990 and 1998 were reviewed for the presence of normal endometrial cells. Chi-square and a power analysis were used to compare these smears with results of smears from women older than 35 years of age with tissue diagnoses other than hyperplasia or carcinoma. All Papanicolaou smears obtained within the 5 years before endometrial sampling were reviewed. Each patient had at least one smear done within the previous 12 months. Clinical information was available for all patients. RESULTS: Of the 201 women in whom endometrial hyperplasia (n = 103) or carcinoma (n = 98) was diagnosed, 4 (2%) had normal endometrial cells in otherwise negative Papanicolaou smears. Of the 289 women in the comparison group, 15 (5%) had normal endometrial cells in their Papanicolaou smears. The prevalence of normal endometrial cells did not differ significantly between the two groups (P =.071). The study had 80% power to detect a 5% or greater difference between groups. CONCLUSION: The prevalence of normal endometrial cells in Papanicolaou smears of women with endometrial carcinoma or hyperplasia does not significantly differ from that in women without these conditions. Reporting normal endometrial cells in Papanicolaou smears according to the recommendations of the Bethesda System may lead to unnecessary procedures and patient anxiety.

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OBJECTIVE: We sought to determine whether there have been any significant changes in professional satisfaction among gynecologic oncologists over the past 30 years. METHODS: We mailed surveys to all U.S. gynecologic oncologists belonging to the Society of Gynecologic Oncologists to compile data on demographics, training, motivating factors, overall professional satisfaction, and the effect of managed care. We compared these factors among oncologists who completed training in different years and among different demographic groups. We used calculated confidence intervals to determine statistical significance. RESULTS: We surveyed 767 gynecologic oncologists and received 344 evaluable responses, representing 47% of the total eligible. Results show that neither the factor rated most important in looking for a first job nor the factor rated most important in giving job satisfaction once in a job has changed significantly among gynecologic oncologists over time. In addition, the importance placed on salary has not varied across the fellowship graduate classes, although within each class salary increased in importance from the first job to the current job. Our analysis shows that while male and female gynecologic oncologists are similar in their job satisfaction and practice patterns, men report being sued twice as often as women, and men tend to stay in their first jobs significantly longer than women. We also compare the surveyed academic gynecologic oncologists to the private gynecologic oncologists and show that while overall job satisfaction is similar, their ratings of the factors that provide job satisfaction do differ significantly. Our data show that managed care penetration has increased over time among gynecologic oncology practices and that gynecologic oncologists' job satisfaction ratings tend to decrease with the increase in managed care penetration, although not reaching statistical significance. CONCLUSIONS: Our results show that changes in practice styles since the 1960s have not affected overall job satisfaction among gynecologic oncologists. However, several trends in practice styles can be noted, including differences between sexes, academic versus private physicians, and attitudes about managed care. The survey also suggests that there is interest among gynecologic oncologists in continuing to monitor changes in patterns of practice and satisfaction.

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BACKGROUND: Several studies have shown that nitric oxide (NO)-releasing agents can kill tumor cells. Unfortunately, currently available NO delivery molecules do not target tumor cells preferentially. To exploit the overexpression of glucose transport proteins and the high level of glucose transport characteristics of tumor cells, glucose was conjugated to S-nitroso-N-acetyl-penicillamine (2-gluSNAP) and evaluated for cytotoxicity in human ovarian carcinoma cells. METHODS: The cytotoxicity of 2-gluSNAP and SNAP was assessed by clonogenic cell survival assays performed in A2780S (cisplatin sensitive) and A2780cP (cisplatin-resistant) ovarian carcinoma cells in vitro. Immunoblotting and immunohistochemistry were used to assess the expression of Glut-1 hexose transport protein in the cell lines as well as in paraffin blocks from 28 surgical specimens of epithelial ovarian carcinoma. Apoptosis was assessed by an end-labeling assay. RESULTS: The ovarian carcinoma cell lines consistently were more sensitive to 2-gluSNAP than SNAP alone. The median effective doses (MEDs) for 2-gluSNAP and SNAP in the A2780s cell line were 0.0042 microM and 20.4 microM, respectively. Therefore, 2-GluSNAP was nearly 5000-fold more potent than the NO-donating moiety (SNAP) alone. In the A2780cP cells, the MED for 2-gluSNAP (0.38 microM) was 250-fold lower than that for SNAP alone (100 microM). Immunoblotting and immunohistochemistry studies showed overexpression of Glut-1 in the cell lines and in 23 of 28 epithelial ovarian carcinoma specimens. CONCLUSIONS: The novel glyco-NO conjugate 2-gluSNAP exhibits a much greater cytotoxicity than the parent NO donor without the hexose moiety. These agents have the potential to target tumor cells preferentially, that overexpress Glut-1. This transporter is expressed highly in epithelial ovarian carcinoma.

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OBJECTIVE: The aim of this study was to determine the effects on transfusion rates, perioperative complications, and survival of using intraoperative autologous blood transfusions for patients undergoing type III radical hysterectomy and lymphadenectomy. STUDY DESIGN: A retrospective analysis was conducted on 156 patients treated with type III radical hysterectomy and lymphadenectomy at the University of Miami School of Medicine from 1990 to 1997. One group of patients (n = 50) had intraoperative autologous blood transfusions and the other (n = 106) did not. RESULTS: The group that received intraoperative autologous blood transfusion had a significant reduction in homologous blood transfusions (12% vs 30%; P =.02). Patient demographic data, histologic parameters, and operative factors were similar between the 2 groups. There was a higher percentage of patients with positive pelvic lymph nodes in the group that did not receive intraoperative autologous blood transfusion (10% vs 30%; P =.02). Seven patients in the intraoperative autologous blood transfusion group (14%) died with disease present and all the recurrences in this group were local. CONCLUSION: The use of intraoperative autologous blood transfusions during type III radical hysterectomy and lymphadenectomy appears to be safe and effective without compromising rates and patterns of recurrence.

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OBJECTIVE: The purpose of this study was to determine the clinical relevance of reporting the presence of normal endometrial cells in the Pap smears of women over the age of 35 years and the significance of this practice as it relates to patient management. METHODS: From January 1992 to December 1995, normal endometrial cells were reported in 206 consecutive Pap smears of women over the age of 35 years. Clinical follow-up was available for all patients, including the results of diagnostic procedures whenever performed. RESULTS: Of the 206 women with normal endometrial cells in their Pap smears, 162 presented with the chief complaint of abnormal vaginal bleeding. They were all evaluated by direct endometrial sampling, resulting in detection of 10 endometrial hyperplasias and 7 endometrial carcinomas. The remaining 44 women who were clinically asymptomatic were followed up with only routine annual gynecologic examinations for a minimum of 3 years. All had negative clinical courses. CONCLUSION: Reporting the presence of normal endometrial cells in Pap smears has little, if any, impact on subsequent patient management. Women who present with abnormal uterine bleeding are worked up for endometrial disease regardless of their Pap smear findings. In clinically asymptomatic patients, practitioners may, and in our experience often do, choose to disregard normal endometrial cells in Pap smear reports. The negative follow-up for the asymptomatic women in our study supports this practice. Therefore, reporting the presence of normal endometrial cells in Pap smears is of no clinical relevance and may, in fact, create a management dilemma for clinicians.

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OBJECTIVE: The aim of this study was to generate HPV-16 E7 peptide-specific cytotoxic T lymphocytes (CTLs) in vitro for future adoptive immunotherapy of cervical cancer. METHODS: Peripheral blood mononuclear cells (PBMC) were isolated from HLA-A2+ healthy donors. The PBMCs were incubated with HPV-16 E7(11-20) peptide and varying cytokines in the primary culture. Restimulation was performed weekly with peptide-pulsed, irradiated autologous PBMCs. Alternatively, the PBMCs were depleted of abundant CD4+ cells and stimulated with HPV-16 E7(11-20) peptide-pulsed dendritic cells. Cytolytic activity was determined by a standard 4-h (51)Cr-release assay. RESULTS: After 6 weeks in culture, we were able to establish peptide-specific CTL lines in one of seven donors by incubating PBMCs with HPV-16 E7(11-20) peptide. When we employed autologous peptide-pulsed dendritic cells to stimulate CD8+ cell-enriched PBMCs, we obtained CTL lines in four of seven donors. The primed CTLs were able to lyse the HLA-A2+ and HPV-16+ cervical cancer cell line Caski. SiHa, an HLA-A2-, but HPV 16+, cervical cancer cell line could be lysed only after transfection with HLA-A2. In addition, a high cytotoxicity (>80%) was obtained against peptide-pulsed, but not unpulsed, targets such as autologous Ebstein-Barr virus-immortalized B cells or allogeneic lipopolysaccaride-stimulated PBMCs. DCs were clearly the most potent of all tested antigen presenting cells to stimulate a CTL response in a proliferation assay. CONCLUSION: HPV-16 E7 peptide-specific CTLs could be generated in vitro. A practical protocol to expand the CTLs to a sufficient number for an application in a clinical trial is in progress.

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Cervical cancer is generally a locoregional disease. The endopelvic fascia envelops the cervix in anterior-posterior fashion and serves as a natural barrier. Thus, cervical cancer preferentially grows to the parametria and involves the ureters before it infiltrates the bladder or rectum. Disease stage, grade, cell type, tumor volume, depth of stromal invasion, vascular space invasion, and lymph node status are common prognostic indicators. Irregular vaginal bleeding and discharge are the two most frequent complaints. Although cervical cancer is still staged clinically, data continue to accumulate favoring a conversion to surgical staging to improve accuracy and treatment outcome.

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Cervical cancer is easily recognized when it presents as a visible lesion, but a problem arises when it adopts unusual presentations. Cervical cancer can develop high in the endocervical canal, beyond the reach of cone biopsy. Copious vaginal discharge from cervical adenocarcinoma may lead to a false-negative Papanicolaou (Pap) smear. Treatment of cervicitis can result in a delay in diagnosis. Successful and timely diagnosis and treatment of cervical cancer requires experience and vigilance. Careful intraoperative palpation of the cervix and uterus can help determine the location and extent of the lesion. Flexibility during surgery is required to utilize intraoperative findings and thus optimize treatment. Pitfalls of cervical cancer diagnosis and treatment with actual case presentations are presented along with other special problems in cervical cancer management such as incidental findings of cervical cancer in hysterectomy specimens, treatment of cervical stump cancers, and unusual cervical cancer cell types.

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PURPOSE: A multicenter trial of chemoradiation therapy to evaluate the feasibility of extended field radiation therapy (ERT) with 5-fluorouracil (5-FU) and cisplatin, and to determine the progression-free interval (PFI), overall survival (OS), and recurrence sites in patients with biopsy-confirmed para-aortic node metastases (PAN) from cervical carcinoma. METHODS AND MATERIALS: Ninety-five patients with cervical carcinoma and PAN metastases were entered and 86 were evaluable: Stage I--14, Stage II--40, Stage III--27, Stage IVA--5. Seventy-nine percent of the patients were followed for 5 or more years or died. ERT doses were 4500 cGy (PAN), 3960 cGy to the pelvis (Stages IB/IIB), and 4860 cGy to the pelvis (Stages IIIB/IVA). Point A intracavitary (IC) doses were 4000 cGy (Stages IB/IIB), and 3000 cGy (Stages IIIB/IVA). Point B doses were raised to 6000 cGy (ERT + IC) with parametrial boost. Concomitant chemotherapy consisted of 5-FU 1000 mg/m2/day for 96 hours and cisplatin 50 mg/m2 in weeks 1 and 5. RESULTS: Eighty-five of 86 patients completed radiation therapy and 90% of patients completed both courses of chemotherapy. Gynecologic Oncology Group (GOG) grade 3-4 acute toxicity were gastrointestinal (18.6%) and hematologic (15.1%). Late morbidity actuarial risk of 14% at 4 years primarily involved the rectum. Initial sites of recurrence were pelvis alone, 20.9%; distant metastases only, 31.4%; and pelvic plus distant metastases, 10.5%. The 3-year OS and PFI rate were 39% and 34%, respectively, for the entire group. OS was Stage I--50%, Stage II--39%, and Stage III/IVA--38%. CONCLUSIONS: Extended field radiation therapy with 5-FU and cisplatin chemotherapy was feasible in a multicenter clinical trial. PFI of 33% at 3 years suggests that a proportion of patients achieve control of advanced pelvic disease and that not all patients with PAN metastases have systemic disease. This points to the importance of assessment and treatment of PAN metastases.

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From 1965 to 1995, at the University of Miami/Jackson Memorial Medical Center, 1223 patients with stage IA2, IB, or IIA cervical cancer have undergone a radical hysterectomy. The charts of these patients were reviewed retrospectively for pathology reports showing positive or close surgical margins. Fifty-one of these cases had final pathology results interpreted as close vaginal margins (CVM), which we define as tumor less than or equal to 0.5 cm from the vaginal margins of resection. All slides of blocks with close vaginal margins were found and reviewed by a single pathologist. Twenty-eight (54.9%) had parametrial involvement or positive lymph nodes and received adjuvant radiation therapy (RT). Of the remaining 23 cases, only 6 had other high risk factors, tumor greater than 4 cm, poorly differentiated, greater than 50% invasion, or lymphovascular space involvement. Sixteen of 23 received radiation. The 5-year survival was significantly greater with RT, 81.3%, than without RT, 28.6% (P < 0.05). The recurrence rate was also decreased from 85.7 to 12.5% (P < 0.01). Although present in less than 2% of radical hysterectomy specimens, CVM without other high risk factors may be an important prognostic variable that should be considered when making adjuvant therapy decisions.

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The incidence and prognostic significance of positive intraperitoneal cytology taken during a radical hysterectomy was reviewed. A prospective study looking at intraperitoneal cytology was conducted by using 400 consecutive radical hysterectomies from January 1988 through June 1996. All selected patients had peritoneal washings performed prior to a radical hysterectomy with pelvic and para-aortic lymphadenectomy. A single pathologist reviewed all cytological and histologic specimens. A total of 400 patients were included in the study. Only 7 of 400 (1.8%) had positive intraperitoneal cytology. Four had squamous cell cancer and 3 had adenocarcinoma. Five had stage IB cervical cancer and the remainder were stage IIA. Three had positive nodes. Six of 7 had tumor size greater than 3 cm. Three of 7 had > 50% invasion and 2 of 7 had lymphovascular space invasion. No other risk factors were present in these specimens. Six of 7 recurred within 18 months of surgery. Recurrences were local or retroperitoneal; none were upper abdomen or intraperitoneal. The incidence of positive peritoneal cytology during radical hysterectomy is 1.8%. The cost of these cytology specimens did not offer an advantage to the current surgical-pathological factors used to determine prognosis and adjuvant therapy.

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BACKGROUND: The presence of p53 mutations and associated mutant p53 overexpression has been demonstrated in many cancer systems. Whether the overexpression of mutant p53 represents cause or effect, and whether p53 mutation contributes actively to the malignant phenotype is a matter of controversy. We examined the growth effects of oligonucleotides designed to interfere with p53 expression and/or activity in p53-mutant/overexpressing endometrial cancer cell lines. METHODS: Phosphorothioate oligonucleotides were used to target p53-related sequences in two p53-mutant/overexpressing endometrial cancer cell lines (KLE and RL95-2) and a normal fibroblast control. The ATP cell viability assay was used to measure growth effects after 6-day treatments with 27-mer and 14-mer sense (S) or antisense (AS) phosphorothioate oligodeoxyribonucleotides (oligos) targeting the promoter/ATG region of p53 and/or the p53 consensus (CON) DNA binding sequence. These sequences were designed to interfere with p53 expression and activity, respectively. Random sequences of the p53 27- and 14-mer were used as controls for nonspecific oligo effects, and a normal fibroblast cell line was used to compare oligo effects and serve as a negative p53 immunostaining control. RESULTS: Mean +/- SE IC50 (50% growth inhibition) of the S, AS p53, and p53 CON oligos were 4.2 +/- 1.3, 4.7 +/- 0.9, and 7.6 +/- 1.4 microM, respectively, for the two endometrial cell lines combined. The AS and S p53 oligos demonstrated dose-dependent inhibitory effects in both cell lines, while p53 CON produced variable effects alone and in combination with p53 AS. In KLE, a uniform inhibitory dose response was seen with p53 CON oligos. In RL95-2, the approximate IC50 for p53 CON was 0.5-1.0 microM, but at increasing doses above this, an inverse dose response was consistently observed. Combinations of p53 AS and p53 CON oligos produced predominantly synergistic growth inhibition. Although combinations of p53 AS and p53 CON in KLE were synergistic at low doses, antagonistic effects occurred at higher concentrations. Oligos had little effect on normal fibroblast growth, with calculated IC50 > 16 microM. Equimolar combinations of p53 S and AS were antagonistic, indicating that antiproliferative effects were sequence-specific. Random oligos demonstrated some nonspecific inhibitory effects, with >25% growth inhibition at 16 microM and beyond. Immunoperoxidase staining for mutant p53 after exposure to 16 microM concentrations of p53 AS oligos demonstrated reductions in p53 staining but persistent overexpression relative to wild-type (fibroblast) cells. CONCLUSION: Phosphorothioate oligos directed against p53 sequences in two p53-mutant endometrial cancer cell lines demonstrated antiproliferative effects. Combined anti-p53 and anti-p53 binding site oligos resulted in predominantly synergistic antiproliferative effects. The activity of sense oligos, the variable responses to p53 CON, and the persistent overexpression of mutant p53 at high concentrations of growth-inhibiting anti-p53 oligos suggest that, while promising, the antineoplastic effects of these oligos occur through complex and incompletely understood mechanisms.

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